KR20070090942A - Sustained release formulation comprising bisphosphonate - Google Patents

Abstract

A pharmaceutical composition for parenteral administration of a somatostatin analogue salt of aspartate, e.g. mono-or diaspartate, lactate, succinate, e.g. mono-or disuccinate, acetate, glutamate, e.g. mono-or diglutamate or citrate and water forming a gelling depot system after injection in contact with the body fluid.

Description

Sustained-release formulations containing bisphosphonates {SUSTAINED RELEASE FORMULATION COMPRISING BISPHOSPHONATE}

The present invention relates to liquid pharmaceutical compositions, in particular depot preparations comprising somatostatin analogues, and methods of making such depot preparations.

Depot preparations are typically administered parenterally. The somatostatin depot preparation can be administered by subcutaneous or intramuscular injection through a small gauge needle, or via cannula to a reachable tissue site. However, parenteral administration can be very painful when repeated injections are required. In addition, there may be difficulties with depot preparations that are administered in liquid form to form a solid implant in the body after injection. Often, the solidification process begins in a syringe before injection, resulting in needle clogging. In addition, the depot preparation can include a polymer or polymer mixture that must be dissolved in an organic solvent, for example, more than 50% of an organic solvent. If an organic solvent remains in the injection solution, it can cause severe tissue irritation or necrosis at the site of implantation.

EP 779 805 provides a pharmaceutical composition comprising a soluble peptide salt which forms a gel upon contact with body fluids, and up to 30% by weight (based on the composition) of a pharmaceutically acceptable carrier. The peptides described in EP 779 805 are somatostatin or somatostatin analogs, for example lanreotide.

Surprisingly, the inventors have found that beneficial parenteral somatostatin depot formulations can be obtained from compositions of pH 3 to 7 comprising water and salts of somatostatin analogs without the use of polymers and organic solvents.

In one aspect, the invention provides an aspartate (eg, mono- or diaspartate), glutamate (eg, mono- or diglutamate), succinate (eg, mono- or di-) of a somatostatin analog. Succinate), lactate, acetate or citrate salts and water, and provides a pharmaceutical composition for parenteral administration which forms a gelling depot upon contact with body fluids after injection. The salt: base ratio of the somatostatin analog salt can range from 0.1 to 2, in which case the somatostatin analog salt is dissolved. The pharmaceutical composition has a pH of about 3.0 to 7.0, preferably 4.0 to 6.0, more preferably about 4.0 to 5.0. Optionally, the composition may comprise a pharmaceutically acceptable buffer in an amount to stabilize the pH of about 3.0 to 7.0, preferably about 4.0 to 6.0, most preferably 4.0 to 5.0.

In another aspect, the invention provides an aspartate (eg mono- or diaspartate), glutamate (eg mono- or digglumate), lactate, succinate (eg, somatostatin analog) Mono- or disuccinate), acetate or citrate salts and water, to provide a pharmaceutical composition for parenteral administration at a pH of about 3.0 to 7.0 upon contact with body fluids to form a gelling depot.

Compositions with a pH of about 3.0 to 7.0 provide good solubility and therefore the compositions of the present invention can be stored without precipitation over a long period of time. The composition will be administered to the patient by injection to begin to form a gelling depot upon or after interaction with the patient's body fluids. The gelling depot releases aspartate, lactate, succinate, acetate, glutamate or citrate salts of somatostatin analogs over time in a patient.

In another aspect, the invention

i) aspartate (eg mono- or diaspartate), lactate, succinate (eg mono- or disuccinate), acetate, glutamate (eg mono- or somatostatin analogue) Diglutamate) or citrate salt in water,

ii) optionally, adding a buffer to stabilize the pH of the solution, and

iii) optionally, filling the syringe with the solution

A method for producing a depot preparation is provided.

In another aspect, the invention

i) aspartate (eg mono- or diaspartate), lactate, succinate (eg mono- or disuccinate), acetate, glutamate (eg mono- or somatostatin analogue) Diglutamate) or citrate salt in water (the solution has a pH of 3.0 to 7.0),

ii) optionally, adding a buffer to stabilize the pH of the solution, and

iii) optionally, filling the syringe with the solution

A method for producing a depot preparation is provided.

The present invention relates to the aspartate (eg mono- or diaspartate), lactate, succinate (eg mono- or disuccinate), acetate, glutamate (eg mono-) of somatostatin analogs. Or diglutamate) or citrate salts.

Somatostatin is a tetradecapeptide having the structure:

Of particular interest the somatostatin analogs are described, for example, in WO 97/01579 and WO 97/25977. The somatostatin analogue comprises the amino acid sequence of formula (I):

In the formula,

X ₁ is a group of Chemical Formula a or b,

R ₁ is optionally substituted phenyl, wherein the substituent may be halogen, methyl, ethyl, methoxy or ethoxy,

이며, 여기서 Z₁은 O 또는 S이고,R ₂ is —Z ₁ —CH ₂ —R ₁ , —CH ₂ —CO—O—CH ₂ —R ₁ ,

Wherein Z ₁ is O or S,

X ₂ is an α-amino acid having an aromatic moiety on a C _α side chain or an amino acid unit selected from Dab, Dpr, Dpm, His, (Bzl) HyPro, thienyl-Ala, cyclohexyl-Ala or t-butyl-Ala And the Lys residue in the sequence corresponds to the Lys ⁹ residue of native somatostatin-14.

As used herein, somatostatin analogues are additionally omitted one or more amino acid units and / or replaced by one or more other amino acid group (s), one or more functional groups replaced by one or more other functional groups, and / or one or more groups By straight chain or cyclic peptide comprising the sequence of formula (I) and derived from natural somatostatin-14, replaced by any other isosteric group above. In general, the term includes all modified derivatives of natural somatostatin-14 comprising the sequence of Formula I above, having a binding affinity in the range of nM for at least one somatostatin receptor subtype as defined below.

Preferably, the somatostatin analog is a compound wherein the residues at positions 8-11 of somatostatin-14 are represented by the sequence of formula (I) as defined above.

More preferably, the somatostatin analog is a compound disclosed above comprising a hexapeptide unit, wherein the residues at positions 3-6 of the hexapeptide unit comprise the sequence of Formula (I). Any of those residues at positions 1 and 2 of the hexapeptide unit are known in the art (eg, those disclosed in AS Dutta in Small Peptides, Vol. 19, 292-354, Elsevier, 1993). Or somatostatin hexapeptide, which may be a substituent to Phe ⁶ and / or Phe ⁷ of somatostatin-14.

More specifically, somatostatin analogs are compounds in which the hexapeptide unit is cyclic and has a direct peptide bond, for example, between the α-carbonyl group of the residue at position 6 and the α-amino group of the residue at position 1.

Lys, X ₁ and X ₂ in the sequence of Formula I may be in L form, and Trp may be in D or L form. Trp preferably has a D form.

이다.X ₁ is preferably a residue of formula a or b, and R ₂ is preferably

to be.

When X ₂ comprises an aromatic moiety on the C _α side chain, X ₂ is suitably a natural or non-natural α-amino acid, for example Phe, Tyr, Trp, Nal, Pal, benzothienyl-Ala, Tic And tyronine, preferably Phe or Nal, more preferably Phe. Preferably, X ₂ is an α-amino acid having an aromatic moiety on the C _α side chain.

When R ₁ is substituted phenyl, R ₁ may suitably be substituted by halogen, methyl, ethyl, methoxy or ethoxy, for example with ortho and / or para. More preferably, R ₁ is unsubstituted phenyl.

Z ₁ is preferably O.

Representative compounds of the invention are, for example, compounds of formula II.

In the formula,

X ₁ and X ₂ are as defined above,

로부터 선택되 는 2가 잔기이며, 여기서A is Pro,

Is a divalent residue selected from

R ₃ is NR ₈ R ₉ -C _2-6 alkylene, guanidino-C _2-6 alkylene or C _2-6 alkylene-COOH, R _3a is H or C _1-4 alkyl, or R ₃ Independently have one of the meanings given for R _3b is H or C _1-4 alkyl, R _a is OH or NR ₅ R ₆ , and R _b is — (CH ₂ ) _1-3 — or —CH (CH ₃ ) —, R ₄ is H or CH ₃ , R _4a is optionally ring-substituted benzyl, and R ₅ and R ₆ are each independently H, C _1-4 alkyl, ω-amino-C _{1 -4} alkylene, ω-hydroxy-C _1-4 alkylene or acyl, R ₇ is a direct bond or C _1-6 alkylene, and R ₈ and R ₉ are each independently H, C _1-4 alkyl , ω-hydroxy-C _2-4 alkylene, acyl or CH ₂ OH- (CHOH) _c -CH _2- , where c is 0, 1, 2, 3 or 4, or R ₈ and R ₉ together with the nitrogen atom to which they are attached form a heterocyclic group which may contain further heteroatoms, and R ₁₁ is optionally ring-substituted benzyl, — (CH ₂ ) _1-3 -OH, CH ₂ -CH (OH)-or-(CH ₂ ) _1-5 -NR ₅ R ₆ ,

ZZ _a is a natural or non-natural α-amino acid unit.

ZZ _a may have a D shape or an L shape. When ZZ _a is a natural or non-natural α-amino acid unit, ZZ _a is suitably, for example, Thr, Ser, Ala, Val, Ile, Leu, Nle, His, Arg, Lys, Nal, Pal, Tyr , Trp, optionally ring-substituted Phe or N ^α -benzyl-Gly. When ZZ _a is Phe, its benzene ring may be substituted, for example, with a para position, by NH ₂ , NO ₂ , CH ₃ , OCH ₃ or halogen. When ZZ _a is Phe, its benzene ring is preferably unsubstituted.

와 같은 시스 형태로도 존재할 수 있다. 개별적인 각 기하이성질체 및 이들의 혼합물은 본 발명의 화합물이다.When A comprises a Pro amino acid residue, any substituents present on the proline ring (eg R ₃ —NH—CO—O—, etc.) are preferably at position 4. Such substituted proline residues are not only in trans form,

It can also exist in the form of a sheath such as Each individual geometric isomer and mixtures thereof are compounds of the present invention.

(식 중, NR₈R₉는 헤테로시클릭기를 형성함)인 경우, 이러한 기는 방향족 또는 포화일 수 있고, 1개의 질소, 또는 질소 또는 산소로부터 선택되는 제2 헤테로원자 및 1개의 질소를 포함할 수 있다. 바람직하게는, 헤테로고리기는 예를 들어, 피리딜 또는 모르폴리노이다. 상기 잔기의 C_2-6알킬렌은 바람직하게는 -CH₂-CH₂-이다.A

Where NR ₈ R ₉ forms a heterocyclic group, this group may be aromatic or saturated and may comprise one nitrogen or a second heteroatom selected from nitrogen or oxygen and one nitrogen. Can be. Preferably, the heterocyclic group is for example pyridyl or morpholino. The C _2-6 alkylene of said residue is preferably -CH ₂ -CH _2- .

Any acyl in A as R ₅ , R ₆ , R ₈ and R ₉ is for example R ₁₂ CO- (wherein R ₁₂ is H, C _1-4 alkyl, C _2-4 alkenyl, C _{3 -6} cycloalkyl or benzyl, preferably methyl or ethyl. If R _4a or R _{11 in A} is ring-substituted benzyl, the benzene ring may be substituted as set forth above for ZZ _a .

Particular preference is given to compounds of the formula III in free form, in salt form or in protected form, the synthesis of which can be carried out as described, for example, in WO 2002/10192, which is incorporated herein by reference. .

In the formula,

The arrangement in C-2 is (R) or (S), or a mixture thereof,

R is NR ₁₀ R ₁₁ -C _2-6 alkylene or guanidine-C _2-6 alkylene, and R ₁₀ and R ₁₁ are each independently H or C _1-4 alkyl.

Salts are obtained, for example, by the method described in WO 2002/10192, which is incorporated herein by reference.

Preferably, R is NR ₁₀ R ₁₁ -C _2-6 alkylene. Preferred compounds of formula II are those wherein R is 2-amino-ethyl, ie cyclo [{4- (NH ₂ -C ₂ H ₄ -NH-CO-O-) Pro} -Phg-DTrp-Lys-Tyr (4-Bzl ) -Phe] (hereinafter referred to as Compound A) and cyclo [{4- (NH ₂ -C ₂ H ₄ -NH-CO-O-) Pro} -DPhg-DTrp-Lys-Tyr (4-Bzl)- Phe] is a compound in free form, in salt form or in protected form. Phg means -HN-CH (C ₆ H ₅ ) -CO- and Bzl means benzyl.

Salts of the present invention in protected form correspond to somatostatin analogs in which one or more amino groups are protected and deprotection produces a compound of formula II, preferably a physiologically removable compound of formula II. Suitable amino protecting groups are disclosed, for example, in "Protective Groups in Organic Synthesis", TW Greene, J. Wiley & Sons NY (1981), 219-287, the contents of which are incorporated herein by reference. Included in An example of such amino protecting group is acetyl.

The composition according to the invention may comprise a buffer. Suitable buffers include, but are not limited to, acetate buffers, lactate buffers, glycine buffers and tartrate buffers. The concentration of the buffer may be about 5 mM to 30 mM, preferably about 10 mM to 25 mM.

In another aspect, the present invention provides a pharmaceutical composition in the form of a viscous liquid that can be injected through a needle of 18G to 25G (eg, 20G) using a syringe. The solution has a viscosity of 10 ² to 10 ⁶ mPa.s after sterile filtration through a 0.2 μm filter (having a viscosity of 1 to 10 ⁴ mPa.s), or after sterile filtration and solvent removal by evaporation or sublimation (10 ² to 10 ⁶ mPa.s). ) Can be put in a syringe. The solvent can also be removed after the solution is in the syringe.

The solution in the syringe may be injected subcutaneously, intramuscularly, intradermally or intraperitoneally of the body via a needle (eg, a 20G needle), or administered through a cannula to a tissue site reachable. Upon contact with the body fluids of the patient, gelation depots will form in the appropriate places. Liquid compositions for parenteral administration may be filled in a syringe, preferably with a prefilled syringe with instructions for use.

In another aspect, the present invention provides a depot preparation for long term release of a pharmaceutically active agent. Implants formed after injection into the body can release the active agent over a long period of time. The release period may range from 1 to 90 days, for example 1 to 60 days, for example 30 to 60 days.

The compositions of the present invention are useful for the treatment of known indications of certain active agents. Compositions of the invention comprising aspartate, lactate, succinate, acetate, glutamate or citrate salts of somatostatin analogs may be useful in the following formulations:

a) preventing or treating a disorder comprising or associated with excessive secretion of GH and / or excess IGF-1, for example treatment of terminal hypertrophy, and type I or II diabetes, in particular complications thereof (eg For example, angiopathy, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy and dawn phenomenon, and other metabolic disorders associated with insulin or glucagon secretion, such as obesity (eg , Pathological (morbid obesity, hypothalamic obesity or hyperinsulinic obesity),

b) intestinal skin fistula and pancreatic skin fistula, irritable bowel syndrome, inflammatory diseases such as Grave's Disease, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, dumping syndrome, watery diarrhea syndrome, AIDS Related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors (eg GEP tumors such as VIP species, glucagon species, insulin species, carcinoids, etc.), lymphocyte cancers, eg For example treatment of lymphoma or leukemia, hepatocellular carcinoma and gastrointestinal bleeding, eg variceal esophageal bleeding,

c) inflammatory disorders as specified above, including angiogenesis, inflammatory eye disease, macular edema, eg cystic macular edema, idiopathic cystic macular edema, exudative age-related macular degeneration, choroidal neovascularization-related disorders and proliferative retinopathy Prevention or treatment of,

d) graft vascular diseases, for example in transplantation of the heart, lungs, heart and lungs, liver, kidney or pancreas, such as allograft or xenograft angiopathy, eg graft vascular atherosclerosis Prevention or eradication, or, for example, catheterization or vascular scraping, for example percutaneous transluminal angioplasty, laser treatment, or other invasion that destroys the integrity of the vascular endothelium or endothelium. prevention or treatment of vascular occlusion due to intravenous stenosis, restenosis and / or vascular injury due to an invasive procedure,

e) Somatostatin receptor expressing or accumulating tumors, such as pituitary tumors, such as Cushing's Disease, gastro-enteropancreatic tumors, carcinoid tumors, central nervous system cancer, breast cancer, prostate Cancer (including progressive hormone-refractory prostate cancer), ovarian or colorectal tumors, small cell lung cancer, malignant bowel obstruction, adrenal ganglion, renal cancer, skin cancer, neuroblastoma, chromophila, thyroid carcinoma, myeloma, lymphoma, Hodgkin's lymphoma ( Hodgkin's lymphoma) and non-Hodgkin's lymphoma, bone tumors and metastases thereof, and the treatment of autoimmune or inflammatory disorders such as rheumatoid arthritis, Grave's disease or other inflammatory eye disease.

Preferably, the compositions of the present invention are useful for the treatment of acromegaly, carcinoids and / or Cushing's disease.

The activity and properties of the liquid compositions of the present invention can be confirmed in standard clinical or animal tests.

Of course, the appropriate dosage of the composition of the present invention will depend, for example, on the condition to be treated (eg, disease type or resistance), the drug used, the desired effect and mode of administration.

For compositions of the present invention comprising aspartate, lactate, succinate, acetate, glutamate or citrate salts of somatostatin, about 0.1 to about 100 mg, preferably about 3 to about 1 injection per month Administered at a dosage of about 60 mg, or about 0.01 to about 4 mg, preferably 0.1 to 1 mg (singed once or in divided doses), per kg of animal body weight per month (eg, parenteral). Satisfactory results are obtained). Thus, the dosage per month of aspartate, lactate, succinate, acetate, glutamate or citrate salt of somatostatin analogs suitable for administration to a patient is on the order of about 0.1 mg to about 80 mg.

The present invention relates to the aspartate (eg mono- or diaspartate), lactate, succinate (eg mono- or disuccinate), acetate, glutamate (eg mono-) of somatostatin analogs. Or diglutamate) or citrate salt (salt: base ratio ranges from 0.1 to 2) and water, and has a predetermined pH of 3.0 to 7.0, preferably about 4.0 to 6.0, more preferably about 4.0 to 5.0 It provides a simple pharmaceutical composition having. The salt: base ratio in the range of 0.1 to 2 dissolves the somatostatin analog salt at a given pH, precipitates after contact with body fluids and changes in the surrounding pH once a depot is formed. pH can be stabilized by buffers. The process for the preparation of the composition is carried out simply by adding water to the somatostatin analog salt. The composition shows good solubility at pH about 4.0 to 6.0, thereby preventing, for example, precipitation or needle blockage in a prefilled syringe. No organic solvents are used, which can cause serious side effects when administered.

The following description illustrates the methods and compositions of the present invention.

Example 1

Raw material Weight g Required weight Actual weight Somatostatin Diaspartate 58.8235 0.8 g 0.8 g Water for Injection (WFI) 100 1.36 mL 1.36 mL

A 2 mL solution of the pharmaceutical composition of the present invention was prepared by mixing 0.8 g somatostatin diaspartate with 1.36 mL of water for injection.

Example 2

Release Profile in Rabbits of Drugs Having the Compositions Given in Example 1. The composition was injected parenterally and blood samples were taken several times over a period of 2 months to determine the amount of somatostatin diaspartate.

Example 3

Raw material Required weight Actual weight Somatostatin Di-Succinate 1.0 g 0.999 g Water for Injection (WFI) 1.6 mL 1.6 mL

The di-succinate form of the pharmaceutical composition of the present invention was prepared by mixing 0.999 g of somatostatin di-succinate with 1.6 mL of water for injection.

Example 4

Raw material Required weight Actual weight Somatostatin Di-Glutamate 0.916 g 0.916 g Water for Injection (WFI) 1.44 mL 1.44 mL

The di-glutamate form of the pharmaceutical composition of the present invention was prepared by mixing 0.916 g of somatostatin di-glutamate with 1.44 mL of water for injection.

Example 5

Release Profiles in Rabbits of Drugs Having the Compositions Presented in Examples 3 and 4. The composition was injected parenterally and blood samples were taken several times over a period of two months to determine the amount of somatostatin disuccinate and somatostatin diglutate.

Claims (16)

Mono- or diaspartate, mono- or diglutamate, mono- or disuccinate, acetate or citrate salts of somatostatin analogs and water, and form a gelling depot system upon contact with body fluids after injection Pharmaceutical composition for parenteral administration. PH comprising mono- or diaspartate, mono- or diglutamate, lactate, mono- or disuccinate, acetate or citrate salts and water of somatostatin analogs and forming a gelling depot system upon contact with body fluids after injection Pharmaceutical compositions for parenteral administration of 3.0 to 7.0. The pharmaceutical composition according to claim 1 or 2, wherein the somatostatin analog salt has a salt: base ratio in the range of 0.1 to 2. The pharmaceutical composition of claim 1, having a pH of about 4.0 to 6.0. The pharmaceutical composition of any one of claims 1-4 having a pH of about 4.0 to 5.0. The pharmaceutical composition of any one of claims 1-5, wherein the pharmaceutical composition comprises a pharmaceutically acceptable buffer in an amount to provide a pH of about 3 to 7. 7. The pharmaceutical composition of claim 6, having a pH of about 4.0 to 5.0. The pharmaceutical composition of claim 6 or 7, wherein the pharmaceutically acceptable buffer is selected from one or more of acetate buffer, tartrate buffer, glycine buffer and lactate buffer. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable buffer is an acetate buffer. The pharmaceutical composition of claim 9, wherein the acetate buffer is used at a concentration of about 10 mM to 25 mM. The method of claim 1, wherein the gelling depot system comprises aspartate, lactate, succinate, acetate, glutamate or citrate salt of somatostatin analog in a patient for a prolonged period of 1 to 90 days. Pharmaceutical composition that releases continuously throughout. The pharmaceutical composition of claim 11, wherein the gelling depot system continuously releases aspartate, lactate, succinate, acetate, glutamate or citrate salts of somatostatin analogues in a patient over a prolonged period of 1 to 60 days. Composition. The pharmaceutical composition according to any one of claims 1 to 12, having a viscosity of 1 to 10 ⁶ mPa · s. A prefilled syringe comprising the composition of claim 1 and instructions for use. i) dissolving the mono- or diaspartate, mono- or diglutamate, lactate, mono- or disuccinate, acetate or citrate salts of the somatostatin analog in water, ii) optionally adding a pharmaceutically acceptable amount of buffer, and iii) optionally, filling the syringe with the solution A method of making a pharmaceutical composition according to any one of claims 1 to 13, comprising. i) dissolving the mono- or diaspartate, mono- or diglutamate, lactate, mono- or disuccinate, acetate or citrate salts of the somatostatin analog in water, ii) optionally adding a pharmaceutically acceptable amount of buffer to achieve a pH of 3.0 to 7.0, and iii) optionally, filling the syringe with the solution A method of making a pharmaceutical composition according to any one of claims 1 to 13, comprising.